Lúcio Roberto Requião-Moura

Podocyte Wnt/ß-catenin pathway is activated by integrin-linked kinase in clinical and experimental focal segmental glomerulosclerosis.

BACKGROUND Changes in podocyte phenotype and function are characteristic of proteinuric glomerular diseases. Integrin-linked kinase (ILK) functions as a common downstream effector in proteinuric diseases. In addition, ILK was shown to interact with the Wnt signaling pathway. Here, we investigated ILK expression as well as its involvement with the Wnt signaling pathway in renal biopsies of patients with primary focal segmental glomerulosclerosis (FSGS), and in a correspondent in vivo model of podocyte lesion. METHODS Biopsies from 37 patients with primary FSGS were evaluated by immunohistochemistry for ILK, phosphorylated GSK-3ß (pGSK-3ß) and ß-catenin expression. As experimental model, male Wistar rats received 5 injections of puromycin aminonucleoside (PAN) at 2-week intervals, and their kidneys were evaluated for ILK, P-cadherin and pAkt expression as well as ß-catenin and LEF-1 colocalization. RESULTS Patients presented de novo ILK expression and pGSK-3ß in podocytes. In animals, there was an increase in gene and protein expression of ILK, mainly detected in the podocytes, as well as increased protein expression of pAkt compared with controls. ß-Catenin translocated to the nuclei of podocytes in animals and patients. ß-Catenin colocalized with LEF-1 in the nuclei of podocytes of animals. Gene expression of ß-catenin and P-cadherin in PAN rats was lower compared with controls. CONCLUSIONS Our findings suggest that activation of ILK activated the Wnt signaling pathway in damaged podocytes. This phenomenon could have an important role in development and/or progression of clinical and experimental FSGS.

Effects of ischemia and reperfusion injury on long-term graft function.

BACKGROUND The clinical manifestation of ischemia/reperfusion injury in renal transplantation is delayed graft function (DGF), which is associated with an increase in acute rejection episodes (ARE), costs, and difficulties in immunosuppressive management. We sought to evaluated the DGF impact after renal transplant. METHODS We evaluated a group of 628 patients undergoing deceased donor renal transplantation between 2002 and 2005 at 3 Brazilians institutions to define the main DGF characteristics. RESULTS DGF incidence was 56.8%, being associated with elderly donors (P = .02), longer time on dialysis (P = .001), and greater cold ischemia time (CIT; P = .001). Upon multivariate analysis, time on dialysis >5 years increased DGF risk by 42% (P = .02) and CIT >24 hours increased it by 57% (P = .008). In contrast, DGF was associated with an higher incidence of ARE: 27.7% in DGF versus 18.4% in IGF patients (P = .047). The ARE risk was 46% higher among individuals with DGF (P = .02), 44% among patients >45 years old (P < .001), 50% among those with >5 years of dialysis time (P = .02), and 47% lower among the who were prescribed mycophenolate instead of azathioprine (P < .001). Patients with DGF showed worse 1-year graft function (54.6 ± 20.3 vs 59.6 ± 19.4 mL/min; P = .004), particularly those with ARE (55.5 ± 19.3 vs 60.7 ± 20.4; P = .009). One-year graft survival was 88.5% among DGF versus 94.0% among non-DGF patients. CONCLUSION The high incidence of DGF was mainly associated with a prolonged CIT. There was a relationship between DGF and ARE, as well as with a negative influence on long-term graft function.

Prognostic factors associated with poor graft outcomes in renal recipients with post-transplant glomerulonephritis

Abstract:  Background:  Little data are available concerning post‐transplantation glomerulonephritis (PTx‐GN) and its prognostic factors associated with graft outcomes.

Cytomegalovirus infection in renal transplantation: clinical aspects, management and the perspectives

Cytomegalovirus infection is one of most frequent infectious complications after renal transplantation, and can be classified as primo-infection, when the transmission occurs through the graft, or reactivation, when the recipient is cytomegalovirus seropositive. After transplantation, cytomegalovirus can appear as an infection, when the patient presents with evidence of viral replication without symptoms or disease, which has two clinical spectra: typical viral syndrome or invasive disease, which is a less common form. Their effects can be classified as direct, while the disease is developed, or indirect, with an increase of acute rejection and chronic allograft dysfunction risks. Diagnosis must be made based on viremia by one of the standardized methods: antigenemia or PCR, which is more sensitive. The risk factors related to infection after transplantation are the serologic matching (positive donor and negative recipient) and anti-lymphocyte antibody drugs. One of the strategies to reduce risk of disease should be chosen for patients at high risk: preemptive treatment or universal prophylaxis. Recent clinical research has described ganciclovir resistance as an emergent problem in management of cytomegalovirus infection. Two types of mutation that cause resistance were described: UL97 (most frequent) and UL54. Today, sophisticated methods of immunologic monitoring to detect specific T-cell clones against cytomegalovirus are used in clinical practice to improve the management of high-risk patients after renal transplantation.

Hospital Admission following Acute Kidney Injury in Kidney Transplant Recipients Is Associated with a Negative Impact on Graft Function after 1-Year

The incidence and outcomes of acute kidney injury (AKI) in kidney transplantation are poorly known. Retrospective cohort analysis was performed on the data of all patients (≥3 months after transplantation and ≥16 years of age) admitted to the hospital due to medical or surgical complications from 2007 to 2010. We analyzed 458 kidney transplant recipients, 55.2% men, median age 49 (IQR, 36–58) years, median of 12.5 (IQR, 3–35) months after kidney transplantation; admitted to the hospital due to medical or surgical complications. Most of the patients received a kidney from a deceased donor (62.2%), the primary cause for hospital admission was infection (60.7%) and 57 (12.4%) individuals were diagnosed with acute rejection (AR). The incidence of AKI was 82.3%: 31.9% stage 1, 29.3% stage 2 and 21.2% stage 3. Intensive care unit (ICU) admission (OR 8.90, 95% CI: 1.77–44.56 p = 0.008), infection (OR 5.73, 95% CI: 2.61–12.56, p<0.001) and the use of contrast media (OR 9.34, 95% CI: 2.04–42.70, p = 0.004) were the independent risk factors for AKI development. The mortality rate was 2.1% and all patients who died were diagnosed with AKI. Even after the exclusion of AR cases, at the end of 12 months, the individuals with AKI exhibited higher percent changes in creatinine values when compared with individuals without AKI (9.1% vs. -4.3%; p<0.001). According to KDIGO system, we found a high incidence of AKI among the complications of renal transplantation. As in other scenarios, AKI was associated with renal function loss at 1-year after the hospital discharge.

Should adolescents with glomerulopathies be treated as children or adults

Background: Glomerular diseases are an important cause of end-stage renal disease, especially among young adults. However, clinical and epidemiological surveys involving adolescent populations are scarce. Aim: To determine the pattern of glomerulopathies (GP) in adolescents submitted to renal biopsy. Methods: A retrospective study of patients’ records of the Glomerulopathy Section, UNIFESP (Brazil), was performed Results: Among 72 adolescents (12–18 years) with GP, 15.6 ± 1.5 years, 58.3% females, the most frequent clinical manifestation was nephrotic syndrome (NS, 71%) and focal segmental glomerulosclerosis (FSGS) was the main histological pattern (24%), followed by minimal change disease (MCD, 19.5%). After comparing the main causes of NS in adolescents with those of adults, we found no statistically significant differences in clinical presentation or outcome. Renal failure-free survival of 1 and 5 years for all GP corresponded to 87.9 and 73.6%, respectively (88.5 and 76.3% for NS). Conclusions: NS was the main manifestation; FSGS and MCD were the most common histological diagnoses. Our data suggest the GP and particularly the NS pattern in adolescents is similar to that of adults, pointing to the need for an adaptation in diagnostic and treatment protocols for this age group, a pattern which corresponds more closely to that of adults.

Expanding the pool of kidney donors: use of kidneys with acute renal dysfunction

ABSTRACT Given the shortage of organs transplantation, some strategies have been adopted by the transplant community to increase the supply of organs. One strategy is the use of expanded criteria for donors, that is, donors aged >60 years or 50 and 59 years, and meeting two or more of the following criteria: history of hypertension, terminal serum creatinine >1.5mg/dL, and stroke as the donor´s cause of death. In this review, emphasis was placed on the use of donors with acute renal failure, a condition considered by many as a contraindication for organ acceptance and therefore one of the main causes for kidney discard. Since these are well-selected donors and with no chronic diseases, such as hypertension, renal disease, or diabetes, many studies showed that the use of donors with acute renal failure should be encouraged, because, in general, acute renal dysfunction is reversible. Although most studies demonstrated these grafts have more delayed function, the results of graft and patient survival after transplant are very similar to those with the use of standard donors. Clinical and morphological findings of donors, the use of machine perfusion, and analysis of its parameters, especially intrarenal resistance, are important tools to support decision-making when considering the supply of organs with renal dysfunction.

Presence of arteriolar hyalinosis in post-reperfusion biopsies represents an additional risk to ischaemic injury in renal transplant.

The role of post‐reperfusion biopsy findings as a predictor of early and long‐term graft function and survival is still a target of research.

Deficient of Megalin in Stable Renal Transplanted Patients with Proximal Tubular Dysfunction

Introduction: Renal-transplant patients with stable graft function and proximal tubular dysfunction (PTD) have an increased risk for IF/TA. The morphological features associated with this dysfunction are unknown. Material and methods: 54 renal transplant patients with normal and stable renal function were submitted to a biopsy and had urinary retinol binding protein (uRBP) and renal function assessment. Patients were divided according to uRBP levels: 1, these findings had no association with uRBP levels. Megalin expression was observed at BB of PTC, 13.7% of bxs presented its expression in less than 50% of tubules, 56.8% had in more than 50% of tubules but with discontinuity over the BB and in 29.5% megalin expressed in more than 50% of tubules continuouslly over the BB. Patients who presented uRBP > 0.6 mg/L had lower amount of megalin expression in their biopsies, p=0.007. Cellular RBP expression was observed diffusely over the cytoplasma of PTC, with different intensities. No correlation was found between tubular megalin expression and uRBP values with CRBP expression. Conclusions: Half of renal transplant patients with normal renal function had PTD. The deficiency of megalin expression could be the subjacent functional alteration found in patients with PTD.